7-94398387-T-C

Variant names:

• chr7-94398387-T-C
• rs1801182
• NM_000089.4:c.87T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000089.4(COL1A2):​c.87T>C​(p.Thr29Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 941,242 control chromosomes in the GnomAD database, including 4,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2768 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1418 hom.)
• Consequence: COL1A2 NM_000089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.88
• Publications: 16 publications found

Genes affected

COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, arthrochalasia type, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Ehlers-Danlos syndrome, cardiac valvular type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, PanelApp Australia, Orphanet, G2P
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 7-94398387-T-C is Benign according to our data. Variant chr7-94398387-T-C is described in ClinVar as Benign. ClinVar VariationId is 196205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.87T>C	p.Thr29Thr	synonymous_variant	Exon 3 of 52	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.87T>C	p.Thr29Thr	synonymous_variant	Exon 3 of 52	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18400 AN: 151776 Hom.: 2762 Cov.: 32

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.0710

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0362

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.0590 AC: 10069 AN: 170612 AF XY: 0.0527

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.0550

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.0296

Gnomad NFE exome AF: 0.00948

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0240 AC: 18983 AN: 789352 Hom.: 1418 Cov.: 11 AF XY: 0.0243 AC XY: 9837 AN XY: 404674

African (AFR) AF: 0.259 AC: 3886 AN: 14976

American (AMR) AF: 0.0517 AC: 1485 AN: 28700

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 213 AN: 18290

East Asian (EAS) AF: 0.229 AC: 4797 AN: 20936

South Asian (SAS) AF: 0.0471 AC: 2610 AN: 55470

European-Finnish (FIN) AF: 0.0242 AC: 881 AN: 36336

Middle Eastern (MID) AF: 0.0217 AC: 87 AN: 4014

European-Non Finnish (NFE) AF: 0.00651 AC: 3752 AN: 576478

Other (OTH) AF: 0.0372 AC: 1272 AN: 34152

GnomAD4 genome AF: 0.121 AC: 18451 AN: 151890 Hom.: 2768 Cov.: 32 AF XY: 0.122 AC XY: 9087 AN XY: 74242

African (AFR) AF: 0.331 AC: 13729 AN: 41440

American (AMR) AF: 0.0763 AC: 1165 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.362 AC: 1871 AN: 5168

South Asian (SAS) AF: 0.0704 AC: 339 AN: 4816

European-Finnish (FIN) AF: 0.0315 AC: 332 AN: 10556

Middle Eastern (MID) AF: 0.0390 AC: 11 AN: 282

European-Non Finnish (NFE) AF: 0.0107 AC: 729 AN: 67862

Other (OTH) AF: 0.107 AC: 226 AN: 2106

Alfa AF: 0.0372 Hom.: 1735

Bravo AF: 0.136

Asia WGS AF: 0.242 AC: 828 AN: 3414

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 01, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 17, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2012

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome, arthrochalasia type, 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 04, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1801182; hg19: chr7-94027699;